Transfusion Related Acute Lung Injury (TRALI) is acute lung injury that occurs during or shortly after transfusion, and is the leading cause of mortality associated with transfusion. According to our preliminary data, TRALI may occur in 1:500 high-risk patients who are transfused. This Transfusion Biology and Medicine SCCOR will determine the incidence, epidemiology, and mechanisms of TRALI, in order to provide scientific data to support strategies that will effectively limit this potentially life-threatening syndrome. We propose four interrelated clinical and basic projects that will elucidate the pathogenesis of TRALI, and translate science into practice. Project 1 will determine the incidence of TRALI through implementation of a novel surveillance system that will capture all TRALI cases that occur after transfusion of almost one million units at two large university hospitals. This project will also determine the clinical risk factors associated with TRALI through a large, prospective case-control study at two major university hospitals. Project 2 will determine whether various blood products induce mild to moderate alterations of lung function in healthy, moderately ill, and severely ill patients, and whether the changes are associated with antibody, cytokines or neutrophil priming activity in the blood product. Project 3 will determine the mechanisms of lung injury in mice transfused with monoclonal or polyclonal anti-MHCI and MCHII antibodies, or with plasma from stored blood. In addition, this project will determine the roles of adhesion receptors, chemoattractant receptors, neutrophils and alveolar macrophages in TRALI, and will test a strategy to hasten recovery from TRALI. Project 4 will determine the basic mechanisms of neutrophil adhesion signaling and will study activation of such signaling by plasma from units and recipients with TRALI. The projects are supported by four cores, including a Clinical Skills Development Core to train young investigators in this rich environment. Through these bench-to-bedside collaborations, this SCCOR will develop strategies to limit or even prevent TRALI. (End of Abstract) INDIVIDUAL PROJECTS AND CORE UNITS PROJECT 1: Transfusion-Related Acute Lung Injury: Incidence and Mechanisms (Toy, Pearl) DESCRIPTION (provided by applicant): Project 1 proposes to obtain scientific data to develop strategies that will prevent or reduce transfusion-related acute lung injury (TRALI), the leading reported cause of transfusion-associated mortality. To achieve this goal, we aim to determine the incidence and mechanisms for the syndrome. The incidence of TRALI is underestimated due to lack of a standard definition and lack of an effective surveillance system of large number of transfusions. Our preliminary data indicate the incidence is as high as 1:500 transfusions in high risk patients. Using the new NHLBI Working Group definition, we will determine the actual incidence of clinical TRALI by a novel surveillance system of almost one million transfusions at two university hospitals. The surveillance system will capture all cases. The mechanisms of TRALI are unclear because previous case series did not include appropriate controls. The proposed large, prospective study will enroll concurrent control patients who were transfused but did not develop TRALI. The association of clinical factors will be tested in TRALI cases and controls. We will determine whether patient conditions such as surgery or inflammation predispose patients to developing TRALI. We will correlate the transfusion of anti-HLA, anti-neutrophil and proinflammatory agents in donor blood products with the development of TRALI. We will also determine if there is a correlation between the titer and specificities of anti-HLA and neutrophil antibodies and the development of TRALI. We will determine whether acute neutropenia is pathognomic of antibody-mediated TRALI. The presence of genetic predispositions in TRALI patients will be identified. We will also determine whether leukoreduction removes any risk associated with transfusion of older cellular blood products, by abrogation of cytokines and neutrophil priming activity. Thus, through a large prospective case-control study, we will be able to determine the mechanisms of TRALI. Once this study clarifies the incidence and mechanisms, rational strategies can be developed to limit this potentially life-threatening syndrome. (End of Abstract)